A new role for PGRP-S (Tag7) in immune defense: lymphocyte migration is induced by a chemoattractant complex of Tag7 with Mts1

PGRP-S (Tag7) is an innate immunity protein involved in the antimicrobial defense systems, both in insects and in mammals. We have previously shown that Tag7 specifically interacts with several proteins, including Hsp70 and the calcium binding protein S100A4 (Mts1), providing a number of novel cellular functions. Here we show that Tag7–Mts1 complex causes chemotactic migration of lymphocytes, with NK cells being a preferred target. Cells of either innate immunity (neutrophils and monocytes) or acquired immunity (CD4⁺ and CD8⁺ lymphocytes) can produce this complex, which confirms the close connection between components of the 2 branches of immune response.     

吐鲁番市胃食管反流病发生相关危险因素分析（附280例报道）

目的：探讨280例胃食管反流病（GERD）的分布特点及危险因素。方法：对临床诊断和胃镜确诊的280例GERD患者进行临床和风险因子相关性分析。结果：不论汉族还是维族,男性患者比例均明显高于女性;汉族患者高发年龄段早于维族患者（z=-2．939,P=0．003,）;汉族和维族患者占反流性食管炎和Barrett食管比例分别为42．4％、81_3％及56．5％、18．8％,其中汉族患者Barrett食管比例较高（X2=14．358,P=0．000）;肥胖、习惯性便秘、重体力活动者、饮食习惯不良在维族患者中的比例较高（P〈0．001）。结论：GERD与性别、年龄密切相关,男性多于女性,汉族患者发病年龄高峰旱于维族患者;汉族患者Barrett食管发生比例高于维族患者;肥胖、习惯性便秘、重体力活动、饮食习惯不良可能是GERD尤其是维族人群GERD的危险因素。     

湖南省双季稻生产系统碳效率

提高农作物生产系统的碳效率是实现低碳农业的重要途径之一.本文采用2004—2012年农作物产量、农田作物生产系统农资投入等统计数据,利用生命周期法和投入产出法,对湖南省双季稻生产系统碳排放、碳吸收和碳效率特征及其动态进行估算.结果表明:湖南省2004—2012年双季稻生产系统年均碳排放总量为656.4×107kg CE,其中化肥和农药生产运输碳排放占农资投入碳排放总量的大部分,分别约占70.0%和15.9%,碳排放总量年际间持续降低,年均降低率为2.4%,碳排放强度则表现为增长趋势;湖南双季稻生产系统2004—2012年年均碳吸收总量为1547.0×107kg C,也呈现逐年降低的趋势,年降低率为1.2%,单位面积稻田碳吸收强度则表现为增长趋势;碳生产效率呈现缓慢增加的趋势,碳经济效率随着年份递进增加幅度较大,年均增长率为9.9%,碳生态效率则表现为稳定且较低,保持在2.4kg C·kg-1CE左右.表明湖南近几年双季稻生产系统碳综合效率提高缓慢,降低肥料和农药的投入量,提高利用效率是提高双季稻生产系统碳效率的关键.     

GSK-3β dysregulation contributes to parkinson's-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein

Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson''s disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.After Alzheimer''s disease (AD), Parkinson''s disease (PD) is the second most prevalent neurodegenerative disease, characterized by selective loss of TH+ DA-neurons of substantia nigra (SN) with diminished production of dopamine (DA).¹ Genome-wide studies have identified SNCA and MAPT, genes encoding α-synuclein (α-Syn) and Tau, respectively, as having strong association to the genesis of PD.^{2, 3, 4} Although the precise etiology of PD remains a mystery, SNCA amplifications and mutations directly link α-Syn dysfunction to disease causation,^{5, 6} firmly establishing a role for α-Syn in sporadic and familial PD, respectively. α-Syn can be phosphorylated at several sites,⁷ and the predominance of α-Syn phosphorylated at serine 129 (S129) in Lewy bodies⁸ suggests its phosphorylation status at S129 has an important pathological role. Various PD models have shown that phosphorylation at S219 enhanced α-syn toxicity resulting in accelerated motor abnormalities and loss of DA-neurons.^{9, 10}Fewer studies have examined the role of Tau (or p-Tau) in PD, but interest in the field has grown since completion of several genome-wide association studies. p-Tau has been found to colocalize with α-Syn in tissue from sporadic PD and dementia with Lewy bodies.¹¹ We^{12, 13} and others^14,15 have also identified p-Tau in different brain regions of PD, dementia with Lewy bodies, and AD. High levels of p-Tau have also been observed in vivo in several toxin^{16, 17, 18} and transgenic α-Syn models of PD,^19,20 suggesting that p-Tau may be an important common factor in the neurodegeneration of not only tauopathies but also of synucleinopathies, such as PD.^{21, 22, 23, 24} Most studies to date have focused on the formation and accumulation of Tau and p-Tau in idiopathic PD. Yet several studies have provided evidence that leucine-rich repeat kinase-2 (LRRK2), a kinase, that when mutated is involved in familial forms of PD, can directly interact with, and activate GSK-3β, resulting in increased p-TAU formation.^25,26Among the kinases known to hyperphosphorylate Tau, glycogen synthase kinase-3β (GSK-3β) may be the most important given its ability to phosphorylate Tau at the majority of its serine/threonine sites that cause associated toxicities in AD.^27,28 The importance of GSK-3β is illustrated in that it is embryonically lethal when knocked out in mice. Regulation of GSK-3β is tightly controlled through a series of direct and indirect measures. Direct regulation occurs through autophosphorylation at Tyr216,^29,30 resulting in a kinase-active form, p-GSK-3β-Y216, whereas phosphorylation at Ser9 results in a kinase-inactive state.³¹ The activity of GSK-3β can also be controlled indirectly through binding to inhibitory complexes with other cytoplasmic proteins,^32,33 or through Wnt-mediated sequestration into multivesicular bodies³⁴ resulting in the physical separation of GSK-3β from its cytoplasmic targets. Control of GSK-3β in the normal state is therefore tightly regulated, with its dysregulation and ensuing aberrant phosphorylation of targets being a common occurrence in many diverse diseases. Several studies have shown that GSK-3β is an important mediator in the injury and repair processes of neurons during cross-talk between DA-neurons and reactive astrocytes.^35,36 These studies showed that astrocyte-derived Wnt1 was capable of blocking GSK-3β activation, allowing the nuclear accumulation of β-catenin and subsequent gene expression of β-catenin-dependent targets essential for neuron survival and repair during chemical or metabolic insults. The importance of regulating the active/inactive states of GSK-3β in regard to neuronal stability is further supported through the analysis of conditional (Tet-inducible) transgenic mice expressing a dominant-negative GSK-3β-K85R mutant or expressing the GSK-3β-S9A mutant.^37,38 In these studies, post-natal Tet-regulated expression of either GSK-3β-K85R or GSK-3β-S9A led to neurodegeneration in the cortex, striatum, and hippocampus. What separates our TG PD model from the tet-inducible GSK-3β models is the spatial patterns of transgene expression, which is influenced by the choice of promoters. The Tet-inducible GSK-3β models are expressed using a CAMKII promoter with our human(h) GSK-3β-S9A transgene being expressed under the Thy-1 promoter. CAMKII-driven expression is limited to neurons originating from the forebrain with Thy-1 promoter-driven expression restricted to neurons in all or most brain regions.^39,40 Although promoter choice effecting tissue expression ultimately decides which regions show degeneration, the important message is that both inactive and hyperactive states of GSK-3β reduce neuronal viability.In our past studies in various in vitro and in vivo models of PD and in postmortem PD tissues, we have consistently observed a positive correlation between increased α-Syn and p-Tau levels with increased GSK-3β-Y216 (the kinase-active form of GSK-3β).^{12, 13, 16, 19, 20} In in vitro studies of MPTP-treated SH-SY5Y cells, blockade of GSK-3β with lithium, or with the highly selective non-ATP competitive inhibitor, TDZD-8, prevented the induction of p-GSK-3β-Y216, abolished p-Tau formation, and reversed the accumulation and aggregation of both p-Tau and α-Syn, averting cell death.¹⁶ Other studies using Rotenone or MPTP/MPP+ in chemical PD models, have shown similar results of decreased neuronal viability during treatments accompanied by dose- and time-dependent increases in GSK-3β activation, with decreased cytotoxicity detected when GSK-3β was inhibited or knocked-down through the use of GSK-3β-specific small molecule inhibitors or through RNAi.^41,42 This suggested to us that p-GSK-3β-Y216 may have a contributory role in the pathogenesis of PD. Using a mouse model overexpressing hGSK-3β-S9A under the Thy-1 promoter together with in vitro kinase assays allowed us to discern the role GSK-3β has in the development of PD-like pathology.⁴³ Analysis of our hGSK-3β-S9A mouse model showed here for the first time that upon aging, these mice develop the cardinal features of parkinsonism, manifested as impaired motor behavior, with associated loss of TH+ neurons, reduced DA production, and shrinkage of SN. Invitro kinase assays confirmed that hGSK-3β was capable of phosphorylating α-Syn on Serine 129 together with the known ability to phosphorylate Tau. Remarkably, both α-Syn and Tau influenced the rate and magnitude of phosphorylation of the other by GSK-3β indicating that an intimate physical relationship exist between the trio of PD related proteins. Together, these data shown indicate the importance of GSK-3β activation, in the behavioral and physiological development of PD like pathology in a new mouse model.     

无症状吸烟者的肺功能改变情况分析

目的:探讨烟龄≥15年,日吸烟量≥15支的无症状男性吸烟者的肺功能改变情况。方法:选择男性无症状吸烟者190人及非吸烟者180人,进行肺功能测定,并比较两组人群的肺功能改变情况。结果:吸烟组与非吸烟组比较,肺活量(VC)、用力肺活量(FVC)、第1秒用力呼气容积(FEV1)、Tiffeneau 1秒率(FEV1/VC)结果改变不明显,而Gaensler 1秒率(FEV1/FVC)、最大分钟通气量(MVV)、用力呼气50%肺活量的呼气流量(FEF50%)、用力呼气75%肺活量的呼气流量(FEF75%)、呼出25%～75%肺活量时的平均流量(FEF25%～75%)、肺一氧化碳弥散量(DLCO)结果均有显著降低,有统计学意义。结论:通过对无症状吸烟人群肺功能测定结果进行分析。发现有些吸烟者虽无临床症状,但已经出现了小气道及肺弥散功能的损伤,提醒吸烟者应早期戒烟,关爱自身健康,净化生存环境,提高生活质量。     

Role of bradykinin B1 and B2 receptors in normal blood pressure regulation

With inhibition or absence of the bradykinin B2 receptor (B2R), B1R is upregulated and assumes some of the hemodynamic properties of B2R, indicating that both participate in the maintenance of normal vasoregulation or to development of hypertension. Herein we further evaluate the role of bradykinin in normal blood pressure (BP) regulation and its relationship with other vasoactive factors by selectively blocking its receptors. Six groups of Wistar rats were treated for 3 wk: one control group with vehicle alone, one with concurrent administration of B1R antagonist R-954 (70 microg x kg(-1) x day(-1)) and B2R antagonist HOE-140 (500 microg x kg(-1) x day(-1)), one with R-954 alone, one with HOE 140 alone, one with concurrent administration of both R-954 and HOE-140 plus the angiotensin antagonist losartan (5 mg x kg(-1) x day(-1)), and one with only losartan. BP was measured continuously by radiotelemetry. Only combined administration of B1R and B2R antagonists produced a significant BP increase from a baseline of 107-119 mmHg at end point, which could be partly prevented by losartan and was not associated with change in catecholamines, suggesting no involvement of the sympathoadrenal system. The impact of blockade of bradykinin on other vasoregulating systems was assessed by evaluating gene expression of different vasoactive factors. There was upregulation of the eNOS, AT1 receptor, PGE2 receptor, and tissue kallikrein genes in cardiac and renal tissues, more pronounced when both bradykinin receptors were blocked; significant downregulation of AT2 receptor gene in renal tissues only; and no consistent changes in B1R and B2R genes in either tissue. The results indicate that both B1R and B2R contribute to the maintenance of normal BP, but one can compensate for inhibition of the other, and the chronic inhibition of both leads to significant upregulation in the genes of related vasoactive systems.     

棉叶中棉酚的快速提取与测定方法研究

棉酚(G)及其相关物甲氧基半棉酚(DHG)、半棉酚酮(HGQ)、半棉酚(HG)、杀实夜蛾素(H1-4)等是棉花中重要的抗虫性萜烯类次生物质.利用高效液相色谱法(HPLC)对棉酚及其相关物进行了分离,测定了棉叶中的棉酚含量,讨论了不同的提取方法和测定条件对结果的影响,给出了一套简便、快速的分析测试方法,同时与紫外-可见分光光度法(苯胺法)的结果进行了对比,认为对于棉花的抗虫性的研究来说,HPLC是比较适宜的方法.     

LCAT can rescue the abnormal phenotype produced by the natural ApoA-I mutations (Leu141Arg)Pisa and (Leu159Arg)FIN

To explain the etiology and find a mode of therapy of genetically determined low levels of high-density lipoprotein (HDL), we have generated recombinant adenoviruses expressing apolipoprotein A-I (apoA-I)(Leu141Arg)Pisa and apoA-I(Leu159Arg)FIN and studied their properties in vitro and in vivo. Both mutants were secreted efficiently from cells but had diminished capacity to activate lecithin/cholesterol acyltransferase (LCAT) in vitro. Adenovirus-mediated gene transfer of either of the two mutants in apoA-I-deficient (apoA-I-/-) mice resulted in greatly decreased total plasma cholesterol, apoA-I, and HDL cholesterol levels. The treatment also decreased the cholesteryl ester to total cholesterol ratio (CE/TC), caused accumulation of prebeta1-HDL and small size alpha4-HDL particles, and generated only few spherical HDL particles, as compared to mice expressing wild-type (WT) apoA-I. Simultaneous treatment of the mice with adenoviruses expressing either of the two mutants and human LCAT normalized the plasma apoA-I, HDL cholesterol levels, and the CE/TC ratio, restored normal prebeta- and alpha-HDL subpopulations, and generated spherical HDL. The study establishes that apoA-I(Leu141Arg)Pisa and apoA-I(Leu159Arg)FIN inhibit an early step in the biogenesis of HDL due to inefficient esterification of the cholesterol of the prebeta1-HDL particles by the endogenous LCAT. Both defects can be corrected by treatment with LCAT.